Breaking sarcomeres by in vitro exercise

Orfanos, Zacharias; Gödderz, Markus P. O.; Soroka, Ekaterina; Gödderz, Tobias; Rumyantseva, Anastasia; Ven, Peter F.M. van der; Hawke, Thomas J.; Fürst, Dieter O.

doi:10.1038/srep19614

Cited by 45 publications

(61 citation statements)

References 59 publications

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“…Both proteins were localized in sarcomeric lesions, which were suggested to contribute to (post-exercise) muscle weakness. 15,16,19 Our patient had an autosomal recessive neuromuscular disease caused by a deleterious variant in the human ortholog of the mouse Ky gene. The patient developed early-onset walking difficulties because of foot drop and progressive equinus deformities of the feet.…”

Section: Discussionmentioning

confidence: 96%

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

et al. 2016

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We describe a new early-onset neuromuscular disorder due to a homozygous loss-of-function variant in the kyphoscoliosis peptidase gene (KY). A 7.5-year-old girl with walking difficulties from 2 years of age presented with generalized muscle weakness; mild contractures in the shoulders, hips and feet; cavus feet; and lordosis but no scoliosis. She had previously been operated with Achilles tendon elongation. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Biopsy of the vastus lateralis muscle showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c.1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel showed that KY is predominantly expressed in skeletal muscle in humans. A recessive variant in the murine ortholog Ky was previously described in a spontaneously generated mouse mutant with kyphoscoliosis, which developed postnatally and was caused by dystrophy of postural muscles. The abnormal distribution of Xin and Ky-binding partner filamin C in the muscle fibers of our patient was highly similar to their altered localization in ky/ky mouse muscle fibers. We describe the first human case of disease associated with KY inactivation. As in the mouse model, the affected child showed a neuromuscular disorder -but in contrast, no kyphoscoliosis.

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Section: Discussionmentioning

confidence: 96%

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

et al. 2016

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“…2015b), live microscopy (Orfanos et al . ) or three‐dimensional cell culture (van der Schaft et al . ) will further increase our knowledge on molecular pathways underlying contraction‐related effects and hence our understanding of the health‐beneficial effects of physical exercise.…”

Section: Electrical Pulse Stimulation – An In Vitro Model For Skeletamentioning

confidence: 99%

Electrical pulse stimulation of cultured skeletal muscle cells as a model for in vitro exercise – possibilities and limitations

et al. 2016

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The beneficial health-related effects of exercise are well recognized, and numerous studies have investigated underlying mechanism using various in vivo and in vitro models. Although electrical pulse stimulation (EPS) for the induction of muscle contraction has been used for quite some time, its application on cultured skeletal muscle cells of animal or human origin as a model of in vitro exercise is a more recent development. In this review, we compare in vivo exercise and in vitro EPS with regard to effects on signalling, expression level and metabolism. We provide a comprehensive overview of different EPS protocols and their applications, discuss technical aspects of this model including critical controls and the importance of a proper maintenance procedure and finally discuss the limitations of the EPS model.

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“…Differentiated C2C12 myotubes grown on 6-well plates were stimulated using a Cdish and the C-Pace unit (Ion Optix, Milton) for 10 msec pulses at 10 V. A pulse program of 5 sec at 15 Hz (tetanic hold), 5 sec pause, 5 sec at 5 Hz (twitch contractions) and 5 sec pause was repeated, for indicated durations, as described previously [50]. Myotubes were harvested in PBS and lysed as described above.…”

Section: Electrical Pulse Stimulationmentioning

confidence: 99%

“…Cytoskeleton contraction and damage were triggered in differentiated murine C2C12 myotubes through electrical pulse stimulation (EPS) according to previously established protocols [50]. Subsequently, mechanical stress dependent changes in protein abundance were monitored.…”

Section: Stk38 Expression and Casa Activity Are Regulated Under Mechamentioning

confidence: 99%

The Hippo network kinase STK38 contributes to protein homeostasis by inhibiting BAG3-mediated autophagy

Klimek

Wördehoff

Jahnke

et al. 2018

Preprint

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Chaperone-assisted selective autophagy (CASA) initiated by the cochaperoneBcl2-associated athanogene 3 (BAG3) represents an important mechanism for the disposal of misfolded and damaged proteins in mammalian cells. Under mechanical stress, the cochaperone cooperates with the small heat shock protein HSPB8 and the cytoskeleton-associated protein SYNPO2 to degrade force-unfolded forms of the actin-crosslinking protein filamin. This is essential for muscle maintenance in flies, fish, mice and men. Here, we identify the serine/threonine protein kinase 38 (STK38), which is part of the Hippo signaling network, as a novel interactor of BAG3. STK38 was previously shown to facilitate cytoskeleton assembly and to promote mitophagy as well as starvation and detachment induced autophagy. Significantly, our study reveals that STK38 exerts an inhibitory activity on BAG3-mediated autophagy. Inhibition relies on a disruption of the functional interplay of BAG3 with HSPB8and SYNPO2 upon binding of STK38 to the cochaperone. Of note, STK38 attenuates CASA independently of its kinase activity, whereas previously established regulatory functions of STK38 involve target phosphorylation. The ability to exert different modes of regulation on central protein homeostasis (proteostasis) machineries apparently allows STK38 to coordinate the execution of diverse macroautophagy pathways and to balance cytoskeleton assembly and degradation.Abbreviations: BAG3, BCL2-associated athanogene; CASA, chaperone-assisted selective autophagy; CHIP, carboxy terminus of HSP70 interacting protein; EPS, electrical pulse stimulation; GST, glutathione-S-transferase; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; STK38, serine/threonine protein kinase 38.

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Breaking sarcomeres by in vitro exercise

Cited by 45 publications

References 59 publications

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

Electrical pulse stimulation of cultured skeletal muscle cells as a model for in vitro exercise – possibilities and limitations

The Hippo network kinase STK38 contributes to protein homeostasis by inhibiting BAG3-mediated autophagy

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